The invention relates to new 14,15-cyclopropano steroids of the 19-norandrostane series, their production and pharmaceutical preparations that contain these compounds.
14,15-Cyclopropano steroids of the 19-norandrostane series of general formula I 
as described.
In general formula I, R1 is a hydrogen atom or an alkyl radical with 1-9 carbon atoms,
R2 stands for a hydrogen atom or a methyl group,
R3 and R4, independently of one another, stand for a hydrogen atom, for a hydroxy group, for an acyloxy group xe2x80x94Oxe2x80x94COxe2x80x94R5 with R5 standing for 1-10 carbon atoms, for a carbamoyloxy group Oxe2x80x94COxe2x80x94NHR6, with R6 standing for a hydrogen atom, an alkyl or aryl radical with 1-5 carbon atoms in each case, for a sulfamoyloxy group xe2x80x94Oxe2x80x94SO2xe2x80x94NR7R8 with R7 and R8, independently of one another, in each case standing for a hydrogen atom, an alkyl group with 1 to 5 carbon atoms or together with the nitrogen atom for a pyrrolidino, piperidino or morpholino group, for a grouping xe2x80x94CH2R9 with R9 standing for a hydroxy group, an alkyloxy group with 1-5 carbon atoms, a chlorine or bromine atom, an azido, nitrilo or thiocyano group or for a grouping xe2x80x94SR10 with R10 standing for an alkyl group with 1-5 carbon atoms,
or R3 and R4 together stand for an oxo group,
or R3 and R4, with the inclusion of C-17, form a spirooxirane or a 2,2-dimethyl-1,3-dioxolane,
and the 14,15-cyclopropane ring is arranged either in xcex1- or xcex2-position, whereby R2 is an xcex1-position, if the cyclopropane ring is in xcex2-position and vice versa.
The compounds according to the invention, the new 14,15-cyclopropano steroids of the 19-norandrostane series, have not yet been described. Their biological action is still unknown.
The object of this invention is to make available 14,15-cyclopropano steroids of the 19-norandrostane series of general formula 
and their pharmaceutically acceptable salts as well as a process for their production.
Another object is to make available pharmaceutical preparations that contain at least one compound of general formula I or their pharmaceutically acceptable salts.
In general formula I 
R1 is a hydrogen atom or an alkyl radical with 1-9 carbon atoms,
R2 stands for a hydrogen atom or a methyl group,
R3 and R4, independently of one another, stand for a hydrogen atom, for a hydroxy group, for an acyloxy group xe2x80x94Oxe2x80x94COxe2x80x94R5 with R5 standing for 1-10 carbon atoms, for a carbamoyloxy group xe2x80x94Oxe2x80x94COxe2x80x94NHR6, with R6 standing for a hydrogen atom, an alkyl or aryl radical with 1-5 carbon atoms in each case, for a sulfamoyloxy group xe2x80x94Oxe2x80x94SO2xe2x80x94NR7R8 with R7 and R8, independently of one another, in each case standing for a hydrogen atom, an alkyl group with 1 to 5 carbon atoms or together with the nitrogen atom for a pyrrolidino, piperidino or morpholino group, for a grouping xe2x80x94CH2R9 with R9 standing for a hydroxy group, an alkyloxy group with 1-5C atoms, a chlorine or bromine atom, an azido, nitrilo or thiocyano group or for a grouping xe2x80x94SR10 with R10 standing for an alkyl group with 1-5 carbon atoms,
or R3 and R4 together stand for an oxo group,
or R3 and R4, with the inclusion of C-17, form a spirooxirane or a 2,2-dimethyl-1,3-dioxolane,
and the 14,15-cyclopropane ring is arranged either in xcex1- or xcex2-position, whereby R2 is in xcex1-position, if the cyclopropane ring is in xcex2-position and vice versa.
Most preferred are
17xcex2-Hydroxy-14xcex1,15xcex1-methylenestr-4-en-3-one (J 1129),
17xcex1-hydroxy-14xcex1,15xcex1-methylenestr-4-en-3-one,
17xcex2-hydroxy-15xcex2-methyl-14xcex1,15xcex1-methylenestr-4-en-3-one,
17xcex2-hydroxy-15xcex1-methyl-14xcex2,15xcex2-methylenestr-4-en-3-one,
17xcex2-hydroxy-17xcex1-hydroxymethyl-14xcex1,15xcex1-methylenestr-4-en-3-one,
17xcex1-methoxy-17xcex2-methyloxymethyl-14xcex1,15xcex1-methylenestr-4-en-3-one,
17xcex2-hydroxy-7xcex1-methyl-14xcex1,15xcex1-methylenestr-4-en-3-one,
17,20-isopropylidenedioxy-14xcex1,15xcex1-methylene-19,21-bis-nor-17xcex1-pregn-4-en-3-one,
3-oxo-14xcex1,15xcex1-methylenestr-4-en-17xcex2-yl-sulfamate,
3-oxo-14xcex1,15xcex1-methylenestr-4-en-17xcex2-yl-n-butanoate,
17xcex2-hydroxy-17xcex1-methyloxymethyl-14xcex2,15xcex2-methylenestr-4-en-3-one (J 1222),
17xcex1-ethylthiomethyl-17xcex2-hydroxy-14xcex2,15xcex2-methylenestr-4-en-3-one (J 1411),
17xcex1-chloromethyl-17xcex2-hydroxy-14xcex2,15xcex2-methylenestr-4-en-3-one (J 1364),
17xcex1-azidomethyl-17xcex2-hydroxy-14xcex2,15xcex2-methylenestr-4-en-3-one (J 1370),
17xcex1-bromomethyl-17xcex2-hydroxy-14xcex2,15xcex2-ethylenestr-4-en-3-one (J 1424),
17xcex2-hydroxy-17xcex1-rhodanomethyl-14xcex2,15xcex2-methylenestr-4-en-3-one (J 1470),
17xcex1-cyanomethyl-17xcex2-hydroxy-14xcex2,15xcex2-methylenestr-4-en-3-one (J 1517).
The invention also relates to a process for the production of the compounds according to general formula I and their pharmaceutically acceptable salts, which is characterized in that a compound of general formula II 
in which R1, R2, R3 and R5 have the above-indicated meaning, is produced by enol ether cleavage in a way that is known in the art.
The enol ether cleavage is performed by the action of strong acids, such as sulfuric acid, hydrochloric acid or organic sulfonic acids, on the compounds of general formula I that are dissolved in a suitable organic solvent.
Subjects of this invention are pharmaceutical substances for oral, rectal, subcutaneous, intravenous or intramuscular use, which together with the commonly used vehicles and diluents can contain at least one compound of general formula I or its acid addition salts as an active ingredient.
Pharmaceutical preparations of the invention are produced with the commonly used solid or liquid vehicles and/or diluents and the generally commonly used adjuvants corresponding to the desired type of administration in a suitable dosage and in a way that is known in the art. In the case of a preferred oral form for dispensing, preferably tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions are also prepared as a depot form.
In addition, parenteral dosage forms such as injection solutions or else suppositories are also considered.
Dosage forms as tablets can be obtained by, for example, mixing the active ingredient with known adjuvants, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, explosives such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents that can achieve a depot effect, such as carboxylpolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.
Coated tablets can be prepared analogously by coating cores that are produced analogously to the tablets with agents that are commonly used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. In this case, the coated tablet shell can also consist of several layers, whereby for example, the above-mentioned adjuvants are used.
To improve the taste, the solutions or suspensions with the active ingredient according to the invention can be mixed with substances such as saccharin, cyclamate or sugar and/or with flavoring substances, such as vanillin or orange extract. In addition, they can be mixed with suspension adjuvants, such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoic acid.
The preparation of capsules can be carried out by mixing a pharmaceutical substance with vehicles such as lactose or sorbitol, which then are introduced into the capsules.
The production of suppositories is preferably carried out by mixing the active ingredient with suitable vehicles, such as neutral fats or polyethylene glycols or derivatives thereof.
In addition, the pharmaceutical preparation forms can be percutaneous preparation forms, e.g., transdermal therapeutic systems (TS) or gels, sprays or ointments or intranasal preparation forms such as nose spray or nose drops.
The 14,15-cyclopropano steroids of the 19-norandrostane series of general formula I according to the invention are hormonal (gestagenic- and/or androgenic-acting) compounds.
Thus, for example, the compound of general formula Ixe2x80x94in which R1 and R2 in each case represent a hydrogen atom, R3 means an xcex1-position methyloxymethyl group and R4 means a xcex2-position hydroxy group and the cyclopropano group is arrange din xcex2-positionxe2x80x9417xcex2-hydroxy-17xcex1-methyloxymethyl-14xcex2,15xcex2-methylenestr-4-en-3-one (J 1222), is just as effective in the pregnancy maintenance test in mice as the gestagen norethisterone acetate that is used worldwide for oral contraception.
Another example is the compound of general formula Ixe2x80x94in which R1 and R2 in each case represent a hydrogen atom, R3 represents an xcex1-position hydrogen atom, R4 stands for a xcex2-position hydroxy group, and the cyclopropane ring is in xcex1-positionxe2x80x9417xcex2-hydroxy-14,xcex1,15xcex1-methylenestr-4-en-3-one (J 1129), which in the same test has an approximately 50-fold stronger gestagenic action in comparison to the reference substance norethisterone acetate.
While the substance 17xcex2-hydroxy-17xcex1-methyloxymethyl-14xcex2,15xcex2-methylenestr-4-en-3-one (J 1222) with 52xc2x14% binds to the progesterone receptor of the rabbit uterus (reference substance: progesterone), there is virtually no affinity to the androgen receptor of the rat prostate (reference substance: 17xcex2-hydroxy-17xcex1-methyl-estra-4,9,11-trien-3-one; R 1881).
17xcex2-Hydroxy-14xcex1,15xcex1-methylenestr-4-en-3-one (J 1129), however, shows a 59xc2x17% binding to the androgen receptor, which corresponds to the binding affinity of the naturally occurring male sex hormone testosterone, and a 42xc2x15% binding to the progesterone receptor.
Another example is the compound of general formula Ixe2x80x94in which R1 and R2 in each case represent a hydrogen atom, R3 means an xcex1-position chloromethyl group, R4 stands for a xcex2-position hydroxy group, and the cyclopropane ring is in xcex2-positionxe2x80x9417xcex1-chloromethyl-17xcex2-hydroxy-14xcex2,15xcex2-methylenestr-4-en-3-one (Code J 1364), which binds with 710xc2x180% to the progesterone receptor of the rabbit uterus (reference substance: progesterone).
In the compounds of general formula I according to the invention, these test results open up many possibilities for birth control in men and women, hormone replacement therapy in men and women, or the treatment or hormonally produced diseases in men and women, such as, for example, endometriosis, breast cancer or hypogonadism.
The compounds of general formula I according to the invention are to be explained in more detail in the examples below, but are not limited thereto.